Phase II single-arm \"window-of-opportunity\" study of a combination of obinutuzumab (GA-101) and venetoclax (ABT-199) in relapsed or refractory diffuse large B-cell lymphoma (DLBCL)

Study design

Obinutuzumab will be given i.v. at a dose of 1000 mg on days 1, 8, 15 in cycle 1 and on day 1 of each following cycles. Venetoclax will be given at 800mg daily p.o. One cycle is 21 days.
This combination treatment will be repeated for up to 3 cycles.
Eligible patients will then proceed to stem cell transplantation.
A 9 cycles (27 weeks) maintenance phase with obinutuzumab and venetoclax will be given in patients ineligible for transplant.
The study will have a 6 patient run-in phase to determine safety and to adjust treatment. After 10 patients a futility analysis is planned.
A Data Safety Monitoring Board (DSMB) will review the safety data once the study is opened.

The first response assessment (including PET-CT) will be performed after the first cycle of obinutuzumab + venetoclax and patients with at least stable disease (SD) or better will be given another 2 cycles of therapy and then have assessment after a total of 3 cycles. Patients with complete or partial remission (CR, PR) after 3 cycles of therapy will either go on to transplant or receive 9 further cycles of the combination therapy (if transplant ineligible). In this case assessments will be performed after 6, 9 and 12 cycles.
Patients with progressive disease at any time-point or stable disease after 3 cycles will be taken off study.

Objectives

Primary objective:
• To evaluate clinical activity and tolerability of obinutuzumab in combination with venetoclax in patients with relapsed/refractory DLBCL

Study design

This is a randomized, 2-arm phase II, multi-center study to evaluate overall response rates in newly diagnosed, transplant ineligible patients receiving 9 cycles induction therapy with either KTd or KRd followed by randomization to either Carfilzomib
maintenance treatment or observation only.
The patient population will consist of adult male and female patients with newly diagnosed multiple myeloma (MM), who are not eligible for or not willing to undergo autologous stem cell transplantation.
Treatment will be discontinued in case of progressive disease, in case of no response after 4 cycles, or due to intolerance.
A safety analysis will be conducted after 10 patients completed at least two cycles of KRd or KTd.

Objectives

Primary objective: To show non-inferiority with respect to response rates between KTd and KRd: to determine ORR in patients after receiving 9 cycles induction therapy with either carfilzomib in combination with thalidomide and dexamethasone or carfilzomib in combination with lenalidomide and dexamethasone

Secondary objectives:
• Feasibility, safety and efficady of a K monotherapy maintenance
• PR, VGPR, CR, sCR, MDR according to IMWG
• PFS of induction arm with or without maintenance
• OS of patients reveiving either KTd vs. KRd induction therapy
• Quality of Life
• Safety and tolerability of KTd and KRd

Study design

This study is an open label, multicenter study. Subjects are randomized at a 1:1 ratio to receive either (arm A) cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or (arm B) romidepsin administered IV at day 1 and day 8 in combination with CHOP administered every 3 weeks for 6 cycles in patients with previously untreated peripheral T-cell lymphoma.

Study design

All patients will undergo standard systemic therapy for metastatic colorectal cancer. Patients in the care-as-usual group are not actively encouraged to change their physical activity level e.g. to start a fitness program during chemotherapy.

The physical exercise ACTIVE-program describes a 12-week exercise program consisting of a combination of a bi-weekly aerobic exercise (cycle ergometer) supervised by a physical therapist and a self-paced increase in physical activity during daily life using a pedometer with a daily step goal as a motivational tool. The program will be individually tailored to each patient based on the training protocol and is aimed at increasing physical activity levels and cardiorespiratory fitness.

Inclusion criteria (part)

• Written informed consent according to ICH/GCP regulations before randomization.
• Patient with histologically or cytologically confirmed colorectal carcinoma (CRC) required to start palliative first-line systemic therapy for inoperable or metastatic disease.
• Patients who were diagnosed with histologically or cytologically confirmed non-metastatic CRC earlier and now relapsed with metastatic disease are also eligible, if any prior neoadjuvant or adjuvant chemotherapy has been completed more than 4 months before inclusion into this trial.
• Patient has measurable disease on CT scan or MRI to be performed within 4 weeks before randomization (measurability criteria according to RECIST 1.1 [1], non-nodal lesions ≥ 10mm, lymph nodes ≥ 15mm OR evaluable disease i.e. patient with nonmeasurable metastases but elevated serum tumor-marker (CEA at least >2xULN).
• Command of written and spoken language allowing for informed consent and for filling in trial questionnaires.
Baseline patient-reported outcomes (PROs) have been completed.
• WHO performance status 0-2.
• Age 18-75 (80) years (if WHO is 0-1 upper age limit is 80 years)

Study design

Subjects meeting all inclusion criteria will be enrolled receiving ixazomib on days 1, 8, and 15 in combination with carboplatin on days 1, 8, and 15. Cycles will be repeated every four weeks.

Phase I:
The phase I part of this study uses an alternate dose escalation accelerated titration design. In the accelerated dose-escalation phase a single-patient cohort per dose level will be enrolled, until one dose limiting toxicity (DLT) or 2 moderate toxicities are observed during cycle 1, or until dose level 4 is reached. At this dose level the cohort is expanded to three patients and dose escalation reverts to a conventional 3+3 escalation design.
DLTs are defined as inability to deliver the drug combination of ixazomib and carboplatin due to drug related toxicity :
• grade 3 or 4 non-hematologic toxicity excluding alopecia
• polyneuropathy greater or equal grade 3
• neutropenia grade 4 for more than 7 days
• neutropenia grade 4 with fever greater than 38.5C
• thrombocytopenia grade 4
• thrombocytopenia grade 3 with bleeding
Moderate toxicities are defined as:
• any grade 2 non-hematologic toxicity excluding alopecia
• any grade 3 hematologic toxicity
The maximum-administered dose (MAD) is defined as the dose at which DLT occur in at least two of six patients treated at that dose level. The dose just below the MAD is considered the maximum-tolerated dose (MTD), providing that DLT is observed in fewer than two of six treated patients (or fewer than one third if more than six patients will be treated) at that dose level. Determination of MAD and MTD is based on DLT observed during the first treatment cycle.

Phase II:
After establishing MTD in phase I, accrual continues to evaluate the efficacy and safety of the combination. A total of 35 patients will be included (patients enrolled in the phase I part within the conventional dose escalation phase at the dose level considered as the MTD may be included).

All subjects will continue on study drugs until disease progression, unacceptable toxicity or treatment discontinuation for any other reason.

Inclusion criteria (part)

Each patient must meet all of the following inclusion criteria to be enrolled in the study:
• Signed informed consent prior to any study-specific procedure
• Female patients, age ≥ 18 years
• Women of childbearing potential must have a negative pregnancy test at screening and must use effective contraception during the study and for a period of 90 days following the last administration of study drug
• Metastatic or locally advanced (without curative loco-regional treatment options with curative intention) adenocarcinoma of the breast, histologically confirmed
• Triple negative subtype defined as the absence of staining for estrogen receptor (IHC <1%), progesterone receptor (IHC <1%) and HER2/neu (IHC 1+ or ISH ratio of < 2.0 between Her2 gene copy number and centromere of chromosome 17 or a copy number of 4 or less)
• At least one prior line of chemotherapy for metastatic or locally advanced disease or disease progression within 12 months of completion of adjuvant chemotherapy
• Documented disease progression
• At least one measurable lesion according to RECIST 1.1 criteria
• Life expectancy of at least 12 weeks
• Performance status ECOG 0-2
• Adequate left ventricular ejection fraction at baseline, defined as LVEF ≥ 50% by either echocardiogram or MUGA
• Peripheral neuropathy NCI CTCAE grade ≤ 1 or grade 2 if no pain on clinical examination
• Adequate hematological, liver and renal function

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A "window of opportunity" trial with Brentuximab Vedotin and Imatinib in patients with relapsed or refractory ALK+ anaplastic large cell lymphoma or patients ineligible for chemotherapy

Study design

This is an open label pilot study of combining BV in a licensed indication with imatinib in patients with ALCL. It is intended as a "window of opportunity" trial in which the study drugs will be given as an initial substitute for conventional chemotherapy with the intention to achieve a remission enabling the patients to proceed to autologous or allogeneic stem cell transplantation, if eligible.
Patients will be included in this trial if they have relapsed or refractory ALK+ ALCL after at least one line of conventional chemotherapy or if they are ineligible for conventional chemotherapy.
Imatinib will be given continuously starting from day 1 of the first cycle at an oral dose of 100mg daily. The dose will be increased to 200mg daily starting from day 1 of the second cycle if no DLT occurs during the first cycle. BV will be given 3 weekly starting on day 1 at a dose of 1.8 mg/kg body weight. In the absence of a dose limiting toyicity (DLT) i.e. haematological toxicity ≥ grade 2, non- haematological toxicity ≥ grade 3, after 3 weeks of therapy, and in the presence of a clinical response (CR or PR) after cycle 1, the BV dose will continue every 3 weeks for 48 weeks. (Figure 2) Dose modifications and stopping rules will be introduced as described in chapter 6. In case of progression at any time during the study the patient will go off trial and receive salvage treatment.

Objectives

Primary objective:
To determine the safety and tolerability of simultane-ous administration of brentuximab vedotin and imatinib mesylate in substitution of conventional chemotherapeutic treatment.

Study design

This is an open phase II, single-arm, multi-center study to evaluate progression free survival in patients receiving ixazomib in combination with thalidomide and dexamethasone (ITD) followed by an ixazomib maintenance phase of a maximum period of 12 months.
The patient population will consist of adult male and female patients with multiple myeloma (MM) with relapsed and/or refractory disease after at least one prior treatment line.
In case of enrollment patients will receive ixazomib 4.0mg at days 1, 8, 15, thalidomide 100mg at days 1 to 28 (50mg in patients aged ≥75 years), and dexamethasone 40mg (20mg in patients aged ≥75 years) at days 1, 8, 15 of a 28-day treatment cycle. The proposed number of cycles is 8. Treatment will be discontinued in case of progressive disease or in case of no response after 4 cycles (≤ SD after 4 cycles). After discontinuation of therapy an end of treatment visit (EOT) will be performed within 14 days after the last dose of the last combination treatment cycle.
After 8 cycles of ITD therapy, maintenance treatment with 4.0mg ixazomib (3.0mg in patients aged ≥ 75 years at first day of maintenance phase) on days 1, 8, 15 of 28-day cycles will be administered to patients with ≥ MR for a maximum period of 12 months. Patients who completed less than 8 cycles of ITD treatment do not qualify for maintenance phase.
Follow-up visits will be performed in 3-monthly intervals until the last patient on ixazomib maintenance therapy has concluded or discontinued the maintenance phase.
A safety analysis will be conducted after enrollment of the first 6 patients and completion of at least two cycles in every patient.

Objectives

Primary
• To determine progression-free survival in patients with relapsed/refractory multiple myeloma receiving ixazomib in combination with thalidomide and dexamethasone for 8 cycles followed by an ixazomib maintenance phase of a maximum period of 12 months.

Secondary
• To determine overall response rate (ORR) in patients with relapsed/refractory multiple myeloma receiving ixazomib in combination with thalidomide and dexamethasone followed by an ixazomib maintenance phase of a maximum period of 12 months. ORR will be assessed according to International Myeloma Working Group (IMWG) criteria, including Minor Response (MR) according to European Society for Blood and Bone Marrow Transplantation (EBMT) criteria
• To determine Overall Survival (OS) in patients with relapsed/refractory multiple myeloma receiving ixazomib in combination with thalidomide and dexamethasone followed by an ixazomib maintenance phase of a maximum period of 12 months.
• To determine renal response in a subgroup of patients with baseline GFR 15-30ml/min
• To assess safety and toxicity of the combination regimen ixazomib plus thalidomide plus dexamethasone followed by an ixazomib maintenance phase of a maximum period of 12 months.
• To assess prognostic value of risk factors at diagnosis, including clinical assessments, lab values and cytogenetic abnormalities such as translocations t(4;14), t(14;16), ampl1q, del17, del13
• To assess change of quality of life (QoL) of patients undergoing treatment with ixazomib plus thalidomide plus dexamethasone followed by an ixazomib maintenance phase of a maximum period of 12 months by use of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire EORTC QLQ C30/MY-20 module
• To associate possible correlations between altered expressions of specifically selected genes including methylation status of key genes (tumor suppressor, oncogenes, DNA repair, cell cycle control and other) and their response to the treatment regimen detected by gene expression profiling and methylation assays obtained at screening

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One arm, Open label, Interventional, non-comparative Study to assess Changes in Lipids and Lipoproteins in HIV infected Women with Hyperlipidemia after Switch from boosted Protease Inhibitors to Raltegravir

Study design

This is a 24-week, one arm, open-label, interventional, non-comparative muticentre study to evaluate lipid changes in HIV infected women with hyperlipidemia on boosted PI based regimen after switching their boosted PI to raltegravir at standard dosage with 400mg twice daily.

Patients will be offered to switch their protease inhibitor containing regimen to a raltegravir (400mg twice daily, orally) based regimen while maintaining the same background therapy.
Patients will be assessed at baseline, after 4, 12 and 24 weeks.

Changes of ongoing antiretroviral therapy other than the switch from protease inhibitor to raltegravir during the study are strongly discouraged unless required by the study physician. In analogy for patients on lipid lowering agents, a stable regimen for 3 months prior to study entry will be required. Modifications of the lipid lowering therapy during study are discouraged and will lead to exclusion (except reduction due to amelioration of the lipid profile).

Objectives

The objective of the study is to assess the change of lipid profiles, observed in HIV infected women with hyperlipidemia after switch from boosted protease inhibitors to raltegravir.

Fludarabine/Rituximab combined with escalating doses of Lenalidomide in untreated chronic
lymphocytic leukemia (CLL) – a dose-finding study with escalating starting dose of Lenalidomide
and concomitant evaluation of safety and efficacy

Study design

This is a non-randomized, multicenter, open-label, single arm phase II trial in patients with previously untreated CD20-positive CLL.
Eligible patients will receive lenalidomide with a backbone of FR for 6 cycles. Lenalidomide will be increased by dose steps of 5 mg every 28 days in the absence of limiting toxicity. If dose limiting toxicity ensues the patients will be treated with last tolerable dose for the remainder of the 6 treatment cycles.
The first 5 patients will start with dose level 5 mg lenalidomide and further escalating dose.
After the fifth patient is included in the study, enrolment will be interrupted until this patient has finished his first treatment cycle. A safety board will evaluate the toxicities of the first 5 patients. If there are more than 2 patients experiencing a DLT in the first treatment cycle, the starting dose will not be escalated and further 5 patients will be enrolled with a starting dose of 5 mg lenalidomide. If only 2 or less patients experience a DLT in the first treatment cycle, the next 5 patients will start the treatment with 10 mg lenalidomide.

Female subjects of childbearing potential must:
• understand the potential teratogenic risk to the unborn child
• agree to have a medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL (including females of childbearing potential who commit to complete abstinence) details see appendix 6
• agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual contact during the following time periods related to this study: 1) for at least 28 days before starting study drug; 2) while participating in the study; 3) dose interruptions; and 4) for at least 28 days after study treatment discontinuation.

The two methods of reliable contraception must include one highly effective method and one additional effective (barrier) method. Fibronectin Cell Binding Peptide (FCBP) must be referred to a qualified provider of contraceptive methods if needed. The following are examples of highly effective and additional effective methods of contraception:
Highly effective methods:
• Intrauterine device (IUD)
• Hormonal (birth control pills, injections, implants)
• Tubal ligation
• Partner's vasectomy

• Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be considered particularly in patients with neutropenia.
• be informed and understand the potential consequences of pregnancy and the need to notify her study doctor immediately if there is a risk of pregnancy
• understand the need to commence the study treatment as soon as study drug is dispensed following a negative pregnancy test
• understand the need and accepts to undergo pregnancy testing based on the frequency outlined in this protocol
• acknowledge that she understands the hazards and necessary precautions associated with the use of lenalidomide

Male subjects must:
• Understand the need for the use of a condom even if he has had a vasectomy, if engaged in sexual activity with a pregnant female or a female of childbearing potential.
• Agree not to donate semen during study drug therapy and for one week after end of study drug therapy.
• All subjects must
• Agree to abstain from donating blood while taking study drug therapy and for one week following discontinuation of study drug therapy.
• Agree not to share study medication with another person and to return all unused study drug to the investigator

Biomarker directed treatment in metastatic colorectal cancer

Study design

The study will consist of two parts:
• Pre-Screening phase
• Treatment phase for KRAS and NRAS wt patients

Pre-Screening phase:
Central Evaluation of KRAS/NRAS status and ERCC-1 gene expression will be evaluated in a central laboratory.

Treatment phase:
RAS wt patients will be treated with 6 cycles of one of the following regimens chosen for optimization based on patient characteristics (primary treatment phase). Patients with ERCC-1 < 1.7 relative gene expression of ERCC-1 over ß-actin (ERCC-1 low) will be assigned to treatment with mFOLFOX6 in combination with Cetuximab. Patients with ERCC-1 gene expression > 1.7 relative gene expression of ERCC-1 over over ß-actin (ERCC-1 high) will be assigned to treatment with FOLFIRI in combination with Cetuximab.

Study design

Patients with multiple myeloma, meeting all eligibility criteria will be registered on entry and treated with 3 induction cycles with VCD, followed by Cyclophosphamide for stem cell mobilization and collection.
After induction patients will be randomized to compare two intensification regimens VMP vs. HDM (R1), except if a patient will proceed to allogenic SCT. In hospitals with a policy of double intensification, all patients will be randomized at R1 between VMP, 1 HDM and 2 HDM, in order also to evaluate 1 HDM vs. 2 HDM
After intensification treatment there will be a 2nd randomization to compare VRD consolidation vs. no consolidation (R2), followed by Lenalidomide maintenance in both arms.

Objectives

Primary Endpoint:
• For all registered patients: progression free survival (PFS) as defined by time from registration to progression or death from any cause (whichever occurs first)
• For all patients included in R1; PFS as defined by time from randomization R1 to progression or death from any cause whichever comes first
• For all patients included in R2; PFS as defined by time from randomization R2 to progression or death from any cause whichever comes first

Secondary Endpoints:
• Response (PR, VGPR, CR and stringent CR), and improvement of response during the various stages of the treatment
• Overall survival measured from the time of registration/randomization R1/ randomization R2
Patients still alive or lost to follow up are censored at the date they were last known to be alive
• Toxicity

Inclusion criteria (part)

• Patients with a confirmed diagnosis of symptomatic multiple myeloma stage I to III according to the International Staging System ISS, i.e. at least one of the CRAB criteria should be present
• Measurable disease as defined by the presence of M-protein in serum or urine, or abnormal free light chain ratio
• Age 18-65 years inclusive
• WHO performance status 0-3 (WHO=3 is allowed only when caused by MM and not by co-morbid conditions)
• Negative pregnancy test at inclusion if applicable
• Written informed consent

Study design

This is an open label, phase II study to evaluate the capacity of Rituximab (Mabthera®) plus Lenalidomide (Revlimid®) to induce objective responses in patients with MALT lymphoma presenting with measureable disease.

Objectives

Primary Endpoint:
To evaluate the clinical potential of Rituximab plus Lenalidomide to induce objective/histologic responses in patients with MALT lymphoma

Secondary Endpoint:
To evaluate the safety of Rituximab plus Lenalidomide in this patient population.

Inclusion criteria (part)

• Histologically verified diagnosis of MALT lymphoma of any localization
• Measurable disease upon diagnosis or first or greater relapse after local therapy (including gastrectomy or any type of surgery or radiation), prior chemotherapy or HP-eradication. In addition, also patients with gastric MALT-lymphoma judged refractory to HP-eradication by a minimum follow-up of 12 months after successful HP-eradication will be included in the study. Patients with gastric MALT lymphoma and no evidence of HP-infection (as judged by histology and ultimately serology) may be enrolled immediately)
• Ann Arbor Stage I-IV
• In case of prior treatment with Rituximab, the presence of CD20 on lymphoma cells must have been demonstrated before inclusion in the trial.
• ECOG performance status of 0,1 or 2
• Age > 18 years
• Life expectancy of at least 3 months
• Patient must be able to take aspirin daily as prophylactic anticoagulation (patients intolerant to ASA (may use warfarin or low molecular weight heparin)
• Hematological test results within these ranges:
Absolute neutrophil count > 1000/µl, Platelet count > 60 x 109/L
• Adequate cardiac, renal and liver function tests (LVEF > 50%, serum creatinine < 2.5mg/dl, ALAT or ASAT < 2.5 x upper limit of normal range, alkaline phosphatase < 2.5 x upper limit of normal range, serum bilirubin < 2.0 mg/dl)
• Patient must be willing and able to comply with the protocol for the entire study duration

• Female subjects of childbearing potential must:
- understand the potential teratogenic risk to the unborn child
- agree to have a medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL (including females of childbearing potential who commit to complete abstinence)
- agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual contact during the following time periods related to this study: 1) for at least 28 days before starting study drug; 2) while participating in the study; 3) dose interruptions; and 4) for at least 28 days after study treatment discontinuation. The two methods of reliable contraception must include one highly effective method and one additional effective (barrier) method. FCBP must be referred to a qualified provider of contraceptive methods if needed. The following are examples of highly effective and additional effective methods of contraception:

Additional effective methods:
Male condom
Diaphragm
Cervical Cap
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased risk of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics should be considered particularly in patients with neutropenia.

- be informed and understand the potential consequences of pregnancy and the need to notify her study doctor immediately if there is a risk of pregnancy
- understand the need to commence the study treatment as soon as study drug is dispensed following a negative pregnancy test
- understand the need and accepts to undergo pregnancy testing based on the frequency outlined in this protocol
- acknowledge that she understands the hazards and necessary precautions associated with the use of lenalidomide

Male subjects must:
Understand the need for the use of a condom even if he has had a vasectomy, if engaged in sexual activity with a pregnant female or a female of childbearing potential.
Agree not to donate semen during study drug therapy and for one week after end of study drug therapy.

All subjects must:
Agree to abstain from donating blood while taking study drug therapy and for one week following discontinuation of study drug therapy.
Agree not to share study medication with another person and to return all unused study drug to the investigator

Pharmacokinetics and metabolic activation of capecitabine when given concomitantly with oxaliplatin and the monoclonal antibody cetuximab

Study design

This study is designed as a multicentre, randomised phase II trial with 24 first-line patients with metastatic K-ras wild-type CRC patients.
Patients with histologically confirmed, K-ras wild-type CRC without previous chemo-therapy for metastatic disease will be screened for this study.
Patients will be randomized in a ratio of 1:1 into two groups:

This PK study has a prospective cross over design with patients serving as their own controls to minimize problems associated with inter patient variability.

Objectives

The objective of this pharmacokinetic study is to exclude a possible influence of CETUX on the plasma disposition and metabolic activation of CCB and when this regimen is given combined with OxPt.
1st objective:
investigation of a possible modulation of co-administered CETUX on the metabolic activation of CCB

2nd objective:
investigation of a possible modulation of co-administered CETUX on the metabolic activation of CCB, when administered concomitantly with OxPt

Study design

This is a randomized trial. It will start at one site, but after enrolment of the first 10 patients, other eligible sites can participate.

All patients will be screened for their physical ability to complete the interventional exercise program. Only patients capable and willing to take part in this study and meeting all inclusion and exclusion criteria will be randomized. Randomization will be stratified according to BMI. All patients are to receive identical counseling for ideal nutritional / life-style / physical activity.

Patients randomized to Arm 2 will additionally undergo a controlled and observed program of physical activity for a period of 6 months. Thereafter the patients are expected to adhere to a comparable; unobserved exercise program at home.

Patients will be followed-up routinely according to the stage of their disease and medical needs. Apart from examinations in the screening phase and after 1 year as well as assessment of laboratory parameters at 3, 6 and 9 months, no additional visits outside of routine visits will be required for study participants.

Patients in Arm-2 will additionally be required to adhere to the time points of the con-trolled/observed physical activity schedule.

Objectives

Primary objective
The primary objective of the study is the individual maximum power output in watt (Pmax) on a bicycle ergometer after 6 months of controlled or unobserved physical activity.

Inclusion criteria (part)

• Signed informed consent
• Postmenopausal women with hormone Rec.pos. breast cancer, who are treated with aromatase inhibitors
• Patients must be able and willing to fill out repeated questionnaires on QOL.
• on lifestyle and sports habits, as well as to adhere to the physical activity program
• Patients must fulfill all screening criteria
• ECOG performance status <= 2
• all age groups

Inclusion criteria (part)

· Histologically confirmed squamous cell carcinoma (including basaloid-squamous cell and
adenosquamous carcinoma) or adenocarcinoma of the thoracic esophagus or the esophagogastric
junction (from 5 cm below the entrance of the esophagus into the thorax to the gastric cardia
(=esophagogastric junction), types l and II according to the Siewert classification).
· Resectable, locally advanced disease (the stage is determined by the combination of CT scan,
EUS and PET and by a multidisciplinary team discussion): T2 N1-3 or T3 Nany or T4a Nany if
technically resectable with curative intent (R0) as decided by a multidisciplinary team discussion
· Health status: WHO performance status ≤ 1
· Patient is considered operable (appropriate organ functions)

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Double blind randomized phase III study of Lenalidomide (Revlimid®) maintenance versus Placebo in responding elderly patients with DLBCL and treated with R-CHOP in first line

Study design

This study is a multicenter randomized phase III study of lenalidomide (Revlimid®)
maintenance versus placebo administered daily for 3 weeks followed by one week rest
for 24 months (26 cycles) in patients responding to R-CHOP/R-COMP for a CD20+ DLBCL.

Patients should have received at least 6 cycles of R-CHOP/R-COMP regimens and up to 8 cycles of
R-CHOP/R-COMP repeated every 2 or 3 weeks according to local preferences.

Objectives

The primary objective is to determine the benefit estimated by the progression-free
survival associated with lenalidomide maintenance compared to placebo in responding
patients treated in first line with R-CHOP or R-COMP for diffuse large B-cell lymphoma

The secondary objectives are to assess:
- percentage of patients who convert from PR to CR
- efficacy according to the response to R-CHOP/R-COMP
- Overall survival in both groups of patients (with and without lenalidomide maintenance)
- Safety of lenalidomide in maintenance-CHOP/COMP in first line

Inclusion criteria (part)

For patients registered at the time of initial diagnosis:
• Patient with histologically proven CD20+ diffuse large B-cell lymphoma (DLBCL)
(WHO classification 2008) including clinical subtypes (primitive mediastinal,
intravascular, etc.). Patients with De Novo Transformed DLBCL from low grade
lymphoma (Follicular, other..) may also be included. Patients with DLBCL
associated with some small cell infiltration in bone marrow may also be included
- Or CD20+ B-cell lymphoma with intermediate features between DLBCL and
Burkitt or with intermediate features between DLBCL and classical Hodgkin
lymphoma
- Or CD20+ Follicular lymphoma grade 3B
- Or CD20+ Agressive B-cell lymphoma unclassifiable
• Previously untreated with chemo- or radiotherapy

For patients registered after response evaluation to first line treatment with R-CHOP/R-COMP:
• same as above
• Have reached a CR or PR (Cheson 2007) after first line treatment with at
least 6 cycles of R-CHOP/R-COMP-14 regimens and up to 8 cycles of R-CHOP/R-COMP-21
• Previously untreated with Radiotherapy

For all patients:
• Aged from 60 to 80 years at time of registration
• aaIPI >=1 at time of initial diagnosis

A Phase I/II Study of Lenalidomide in Patients with Chronic Myelomonocytic Leukemia

Study design

This is a phase I/II, open-label, dose-escalation study of lenalidomide in patients with CMML. In phase I of the study the primary purpose is to determine the MTD. A total of 30 patients is planned to be included. Pretreatment is permitted.

Objectives

Phase I trial:
Primary objectives:
The primary objective of the phase I trial is to determine the MTD (maximum tolerated dose) of lenalidomide.
Secondary objectives:
Secondary objectives include the evaluation of safety and tolerability.

Phase II trial:
Primary objectives:
The primary objective of the phase II trial is to determine the hematologic response achieved with lenalidomide administered in subjects at the MTD determined in phase I.
Secondary objectives:
The secondary objectives focus on achieving transfusion independence and cytogenetic response. In addition, progression free survival and overall survival will be
determined.

Inclusion criteria (part)

CMML according to the WHO diagnostic criteria
All previous cancer therapy must have been discontinued at least 4 weeks prior to treatment in this study. Patients carrying a somatic mutation involving the platelet derived growth factor receptor beta (PDGFRB) can be included if standard treatment with imatinib failed.
No prior use of lenalidomide.

Phase II Study to Investigate the Treatment of Patients with NSCLC Stage IIIB and IV without the Option of Surgery with a Combination of Cisplatin, Docetaxel and Bevacizumab

Study design

Objectives

Primary endpoint
The primary objective of this proof-of-concept study is to determine the objective response rate of patients treated within the study protocoll. This response rate will be compared to historical data from the ECOG4599 and AVAiL trials.
Secondary endpoints
Progression free survival, defined as the duration of time from first study treatment until progression or death from any cause as documented by the investigator.
Overall survival; Duration of response; Overall toxicity according to NCI-CTC criteria.

Study design

Phase III, randomized CLL Patients with a PR or CR after a Rituximab containing induction treatment will be randomized to treatment with Rituximab every 3 months for 24 months or observation for 24 months

Phase I/II Trial of Lenalidomide in Combination with Vorinostat and Dexamethasone as Therapy in Relapsed or Refractory Patients with Peripheral T-Cell Non-Hodgkin Lymphoma (PTCL)

Study design

Non-randomised, open, Phase I/II in a 3+3 design

Objectives

Primary objective:
• To determine the maximum tolerated dose of the Lenalidomide, Vorinostat, and Dexamethasone combination

Secondary objectives:
• To determine the safety of the combination regimen, the remission rate of a combination therapy with Lenalidomide, Vorinostat and Dexamethasone, the median progression free survival, overall survival

Study design

This is a non-randomized, multicenter, open-label, single-arm Phase II study in patients with previously treated metastatic breast cancer. Eligible patients may have no more than 1 line of palliative treatment, however prior therapies must include trastuzumab containing regimens in the adjuvant or metastatic setting

Objectives

Primary Endpoint: to determine the efficacy of a Lapatinib plus Caelyx combination regimen in the treatment of advanced metastatic breast cancer, in terms of overall response rates

Phase 1 study to evaluate the feasibility and efficacy of the addition of P1101 (PEG-Proline-Interferon alpha-2b) to imatinib treatment in patients with chronic phase chronic myeloid leukaemia not achieving a complete molecular response (MR 4.5 or BCR-ABL transcripts not detectable)

Study design

This is a phase 1, open label pilot study of adding P1101 to treatment with imatinib in patients with CML in chronic phase. Patients are eligible, if a molecular remission 4.5 or below has not been achieved with imatinib therapy alone after at least 18 months of therapy. Only patients achieving a CHR and a CCyR at study entry will be included. P1101 will be added in a dose of 50µg subcutaneously every 14 days. In the absence of a dose limiting toxicity (DLT), i.e. haematological toxicity ≥ grade 2, non haematological toxicity ≥ grade 3, after 12 weeks of therapy, P1101 will be increased to 100µg subcutaneously every 14 days (refer to 6.2.). In the absence of a DLT after another 12 weeks of therapy, treatment will be continued with the same dose level for further 12 months. A dose of 100µg every 14 days is considered as maximum dose.
Imatinib will be continued at the same dose level as before study entry.

Objectives

Primary objective:
to determine the safety and tolerability of the addition of P1101 to the currently established dose of imatinib.Secondary objective:
to determine the rate of achievement of ≥ 1 log reduction from the initial BCR-ABL transcript level at study entry and the achievement of molecular remission 4.5 or undetectable BCR-ABL transcripts.

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Capecitabine in combination with Bendamustine in women with pretreated locally advanced or metastatic Her2-negative breast cancer, a Phase II Trial

Study design

This is a non-randomized, multicenter, open-label, single-arm Phase II study in pretreated patients with Her2-negative advanced breast cancer. Prior therapies must include anthracyclines and/or taxans in the adjuvant or metastatic setting. Following a two-stage design efficacy and safety of bendamustine and capecitabine will be evaluated following recruitment of the first 20 patients. Upon favorable results a further 20 patients will be recruited to reach the target population of 40 evaluable patients.

Objectives

Primary objective:
The efficacy of a capecitabine plus bendamustine combination regimen in the treatment of Her2-negative advanced metastatic breast cancer.Secondary objectives:
• To determine the safety profile of a combination with capecitabine and bendamustine in terms of qualitative and quantitative toxicities from first study treatment dose until completion of study treatment due to progression or for any other reason.
• To evaluate the study population with respect to the following: clinical benefit (CR, PR or stable disease for at least 24 weeks), progression free survival (from treatment start until progression or death from any cause) and explorative the overall survival (from treatment start until death from any cause).
• To evaluate Quality of Life (QoL) status within the study population is captured using the EORTC QLQ-C30 standard questionnaire
• Predefined subgroup analysis of triple-negative patients and hormone receptor positive patients in terms of response